Fig. 5: Complex I inhibition in combination with glutaminase deletion impedes Notch1-mutant T-ALL leukemia development, improves tumor burden reduction, and extends overall survival in a murine model.

a Schematic of study design utilizing murine Notch1-mutated GLS fl/fl. b GFP⁺mCD45⁺ leukemia cells (%) in PB from mice bearing murine Notch1-mutated GLS fl/fl T-ALL cells after 5 days of treatment as shown in (a) (mean ± SD, n = 3 individual mice per treatment arm); one-way ANOVA; **p = 0.0025. c GFP⁺mCD45⁺ leukemia cells (%) in BM from mice as in (b) (mean ± SD, n = 3 individual mice per treatment arm); one-way ANOVA, **p = 0.001; and ***p = 0.0005. d GFP⁺mCD45⁺ leukemia cells (%) in spleens from mice as in (b) (mean ± SD, n = 3 individual mice per treatment arm); one-way ANOVA, *p = 0.013. e Spleens harvested from mice bearing murine Notch1-mutated GLS fl/fl T-ALL cells following 5 days of treatment with vehicle; IACS-010759; tamoxifen; or combination of IACS-010759 and tamoxifen (n = 3). f H&E staining of BM, spleen and liver from one representative mouse from each group, selected based on complementary FL results from (c) and (d). Scale bars represent 100 μm; from the same experiment as FL data. g Heatmap of MS analysis of metabolites in PB of mice bearing murine Notch1-mutated GLS fl/fl T-ALL cells after 5 days of treatment with vehicle; IACS-010759; tamoxifen; or IACS-010759 and tamoxifen; (mean log of fold-change ratio over the level of metabolites measured in mice treated with vehicle); (mean ± SD, n = 4 individual mice/group). h Kaplan–Meier survival curves of mice transplanted with murine Notch1-mutated GLS fl/fl T-ALL. Mice (n = 5 per treatment arm) were treated with vehicle; tamoxifen (1 mg/mouse over 5 days); IACS-010759 (5 days per week 5 mg/kg Mo–Fr) or concomitantly with IACS-010759 and tamoxifen; treatment was initiated after detection of GFP⁺ cells in PB by FL at day 7; log-rank test, ***p < 0.005, ****p < 0.0001. i Weekly tumor burden monitoring by detection of GFP⁺mCD45⁺ leukemia cells in PB in mice as indicated in (h); the timeframe of treatment is labeled by the yellow windows on the graph; (mean ± SD, n = 5 individual mice per treatment arm).